(a) 2-Arylalkanoic acids
A variety of 2-arylalkanoic acids are now known to be useful as active anti-inflammatory, analgesic and anti-pyretic pharmaceutical drug products. A few of the better known include the 2-arylpropionic acid derivatives such as fenoprofen which is 2-(3-phenoxyphenyl)propionic acid and related compounds which are described in Marshall U.S. Pat. No. 3,600,437, ibuprofen which is 2-(4-isobutylphenyl)propionic acid and which is described with other related compounds in Nicholson et al. U.S. Pat. No. 3,385,886, naproxen which is 2-(6-methoxy-2-naphthyl)propionic acid which is described with other related compounds in Belgian Pat. No. 747,812 (Derwent Index No. 71729R-B). In addition a large variety of other 2-aryl-C.sub.3 to C.sub.6 -alkanoic acid compounds are described in the medical, pharmaceutical and patent literature including the above patent references as well as Shen U.S. Pat. No. 3,624,142, and Adams et al. U.S. Pat. No. 3,793,457 which patents describe some fluoro-substituted biphenylalkanoic acids. Another compound of interest of this latter type is flurbiprofen which is 2-(2-fluoro-4-biphenylyl)propionic acid. Thus, a large variety of 2-aryl-C.sub.3 to C.sub.6 -alkanoic acids, and particularly the 2-arylpropionic acid drug compounds are known and more of such compounds will undoubtedly be discovered and described in the future patent and other technical literature.
(B) Prior Processes
The above patent references also describe a variety of process routes for preparing useful 2-aryl-C.sub.2 to C.sub.6 -alkanoic acids. However, some of the prior processes suffer a variety of disadvantages including expensive starting materials, dangerous by-products, and gross quantities of by-products necessitating substantial expense in destroying or getting rid of such by-products. As a result chemists skilled in chemical process research continue to study and search for improved processes for making the more economically significant 2-aryl-C.sub.3 to C.sub.6 -alkanoic acids, and particularly the 2-arylpropionic acids.
Among the possible process routes being explored to prepare the useful ester compounds are processes involving the use of trivalent thallium salts as reactants. A. McKillop et al. in the Journal of the American Chemical Society (JACS), 95 (1973) pp. 3340-3343 describe a process for preparing methyl arylacetates by the oxidative rearrangement of acetophenones with thallium (III) nitrate (TTN). Treatment of acetophenone at room temperature with 1 equivalent of TTN in a mixture of methanol and 70% aqueous perchloric acid (5 to 1) resulted in smooth reduction of the TTN to thallium (I) nitrate; precipitation of the inorganic salt was complete after 5 hours. Filtration and evaporation of the filtrate gave an oil which by glpc analysis, consisted of two components in the ratio of 16:1. They were identified as methyl phenylacetate (94%) and .omega.-methoxyacetophenone (6%). Distillation of the mixture gave pure methyl phenylacetate in 84 percent yield. When this process was applied to the oxidation of propiophenone with TTN in acidic methanol a mixture of products was obtained, which consisted of methyl .alpha.-methylphenyl acetate (45%) and .alpha.-methoxypropiophenone (32%).
See also Chemical Abstracts, 82, (1975) page 501, item 16821x (abstracting Japan Kokai 74 48661) which refers to the production of 2-substituted benzothiazolacetic acid esters using perchloric acid-methanol mixtures. However, chemists and engineers concerned with designing large scale chemical processes would prefer to avoid process conditions which would involve the use of perchloric acid-methanol mixtures which are potentially hazardous or explosive. E. C. Taylor and A. McKillop also disclosed a process for preparing methyl 2-phenylpropionate as the only substantial product by reacting propiophenone with anhydrous trivalent thallium trinitrate on a Florisil support at the April, 1974 American Chemical Society (ACS) meeting in Los Angeles and the IUPAC meeting in Belgium in August, 1974, respectively. However, as is apparent from the above reports, working directly with the ketone reactant (here the propiophenone) and trivalent thallium salt in an aqueous organic medium results in a yield lowering mixture of products which chemical process chemists and engineers would prefer to avoid. Also, when the ketone is reacted directly with the anhydrous trivalent thallium salt on a Florisil support (TTN: Florsil=1:2 w/w) a large quantity of the inert Florisil is required because the trivalent thallium salt supported thereon reacts mole for mole (stoichiometric proportions) with the ketone reactant. The reaction in commercial scale operation would thus produce huge quantities of monovalent thallium salt on Florisil support which must be handled or otherwise disposed of, thus inherently increasing the total cost of the process. Those skilled in the chemical process art continue to search for improved, technically practical, economical processes for preparing these valuable drug compounds, which would avoid the above problems.